Bacterial protein synthesis starts with N-formyl-methionyl-tRNA and, as a consequence, all newly synthesized polypeptides contain an N-formyl-methionine terminus (Figure I). Peptide deformylase (PDF) is a metalloenzyme that removes the N-formyl group of the polypeptides as they emerge from the ribosome during the elongation process [Adams, J. M. (1968) J. Mol. Biol. 33, 571-589; Livingston, D. M. and Leder, P. (1969) Biochemistry 8, 435-443; Ball, L. A. and Kaesberg, P. (1973) J. Mol. Biol. 79, 531-537]. Depending on the nature of their second amino acid, polypeptides are further processed by methionine amino peptidase (MAP) to yield the mature protein. Deformylation plays an indispensable role in protein maturation as MAP, an essential enzyme for bacterial growth, cannot hydrolyze N-blocked peptides [Solbiati, J., Chapman-Smith, A., Miller, J. L., Miller, C. G. and Cronan Jr., J. E. (1999) J. Mol. Biol. 290, 607-614].

PDF is ubiquitous in bacteria, with at least one pdf gene present in all bacterial genomes sequenced to date [Guilloteau, J. P., Mathieu, M., Giglione, C., Blanc, V., Dupuy, A., Chevrier, M., Gil, P., Famechon, A., Meinnel, T. and Mikol, V. (2002) J. Mol. Biol. 320, 951-962], and it has been shown to be essential for growth in a number of bacterial species [Mazel, D., Pochet, S, and Marliere, P. (1994) EMBO J. 13, 914-923; Meinnel, T. and Blanquet, S. (1994) J. Bacteriol. 176, 7387-7390; Margolis, P. S., Hackbarth, C. J., Young, D. C., Wang, W., Chen, D., Yuan, Z., White, R. and Trias. J. (2000) Antimicrob. Agents Chemother. 44, 1825-1831; Margolis P., Hackbarth, C., Lopez, S., Maniar, M., Wang, W., Yuan, Z., White, R. and Trias. J. (2001) Antimicrob. Agents Chemother. 45, 2432-2435].
PDF does not play a role in eukaryotic cytoplasmic protein synthesis which does not involve N-formylation, but nuclear-encoded PDF proteins, containing a chloroplast/mitochondria localization signal, have been identified in parasites, plants and mammals, including humans [Giglione, C., Serero, A., Pierre, M., Boisson, B. and Meinnel, T. (2000) EMBO J. 19, 5916-5929]. PDF is essential in plant and parasite organelles [Bracchi-Ricard, V., Nguyen, K., Zhou, Y., Rajagopalan, P. T. R., Chakrabarti, D. and Pei, D. (2001) Arch. Biochem. Biophys. 396, 162-170; Serero, A., Giglione, C. and Meinnel, T. (2001) J. Mol. Biol. 314, 695-708] since their genomes encode for a number of proteins which require deformylation for activity [Giglione, C. and Miennel, T. (2001) Emerging Ther. Targets 5, 41-57], but there is evidence to suggest that this is not the case in animals. In fact, characterization of human mitochondrial PDF has shown that it is much less active than its bacterial counterpart. Furthermore, PDF inhibitors which are active against the human PDF enzyme in vitro have no effect on the growth of normal human cell lines [Nguyen, K. T., Hu, X., Colton, C., Chakrabarti, R., Zhu, M. X. and Pei, D. (2003) Biochemistry 42, 9952-9958].
PDF inhibitors represent a promising new class of antibacterial agents with a novel mode of action covering a broad-spectrum of pathogens. The present inventors have discovered novel compounds, which are inhibitors of PDF activity. Such derivatives are useful in the treatment of bacterial infections associated with such PDF activity.
In light of the above, a need exists to develop PDF inhibitor compounds of the present invention, which has a mode of action that covers a broad spectrum of pathogens, corresponding compositions and treatment methods for bacterial infections.
The present invention is directed to overcoming these and other problems encountered in the art.